Halogenomethylcyclopropanes are important intermediates for the preparation of pharmaceuticals (see, for example, British Patent Specification 1 136 214, U.S. Patent Specification 3 433 791 and EP-OS (European Published Specification) 102 833). As is usual in the preparation of pharmaceuticals, the purity for the intermediates required for this purpose should be as high as possible.
It is known to prepare halogenomethylcyclopropanes by reacting the corresponding alcohols with phosphorus trihalides. In accordance with Eur. J. Med. Chem.-Chim. Therap. 15, 571 (1980), however, a reaction temperature of -10.degree. C. leads to over 70% undesired halogenocyclobutane. Even at temperatures of -65 and -80.degree. C., which are difficult to control from a technical point of view, the undesired halogenocyclobutane still amounts to 8.0 and 4.3%, respectively.
In accordance with a different process, halogenomethylcyclopropanes are prepared by reacting the corresponding alcohols with methanesulphonyl halides in the presence of trialkylamines. This process, however, requires complicated dosing and temperature control (see EP-OS (European Published Specification) 565 826), if moderately pure products are to be obtained. To do this on an industrial scale requires complex measuring and control techniques and the reaction needs to be carried out extremely carefully.
Halogenoalkyls can also be prepared from hydroxyalkyls by reacting these with arylphosphorus halides (see EP-OS (European Published Specification) 251 246), for which purpose triarylphosphorus dihalides are generally employed, from which arylphosphorus tetrahalides are prepared in situ with elemental halogen. This process has not been applied to the conversion of hydroxymethylcyclopropanes into halogenomethylcyclopropanes. Moreover, triarylphosphorus dihalides are not readily accessible.
In the process which has been the most advantageous to date, hydroxymethyl cyclopropane is added to a mixture of hexachloroacetone and triphenylphosphine, obtaining apparently pure chloromethylcyclopropane in yields of 80 to 90% (see J. Org. Chem. 49, 431 (1984)). The same reference describes the preparation of bromomethylcyclopropane by treating a mixture of hydroxymethylcyclopropane, triphenylphosphine and dimethylformamide with elemental bromine. At a reaction temperature of -10.degree. C., the product is said to be free from linear alkyl bromides and bromocyclobutane and can be obtained in a yield of 72%. However, even at room temperature, linear bromobutene is indicated as the main product. Reproduction at -10.degree. C. has revealed that the bromomethylcyclopropane obtained contains 0.6% by weight of linear impurities (see the present Comparison Example 1). In accordance with the reference, a very small excess of bromine is employed (98.9 mmol of bromine per 97.1 mmol of hydroxymethylcyclopropane).
The disadvantages of this process are the purity of the halogenomethylcyclopropane obtained, which is still unsatisfactory, the accessibility and manageability of hexachloroacetate, which are a problem, and the fact that the preparation processes for chloro- and bromomethylcyclopropanes differ. A particular problem is the contamination of the halogenomethylcyclopropanes obtained with linear compounds, in particular 1-halogeno-3-butenes, since the physical properties of linear halogenobutenes are virtually no different to those of the corresponding halogenomethylcyclopropanes. This is why the undesired linear compounds cannot be separated from the desired halogenomethylcyclopropanes by customary methods, for example by distillation.